Granulocyte-macrophage colony stimulating factor (GM-CSF) promotes to proliferate bone-marrow granulocyte and macrophage progenitor cells. It was identified as a humoral factor stimulating colonization of granulocyte and macrophage in vitro. Therefore, the factor is named as Granulocyte-macrophage colony stimulating factor (GM-CSF)
GM-CSF is now known as a stimulating factor for a wide range of cells; inducing differentiation and proliferation of granulocyte-macrophage lineage blood cells, stimulating a function of antigen presenting cells, expressing and maintaining a part of epithelial functions and expressing functions of alveolar macrophage (e.g. stimulating surfactant decomposition, stimulating disinfection capacity, and stimulating Fc receptor expression) (The cytokine handbook, 4th edition (ed.) Thomson, A. et al., Academic Press, 2003).
On the other hand, GM-CSF is known to cause various diseases. GM-CSF induces various diseases, such as 1) allergic disease such as asthma, atopy, and pollinosis, 2) graft rejection, graft-versus-host disease (GVHD), and 3) autoimmune diseases such as rheumatoid arthritis.
For example, an overexpressing hGM-CSF is detected in a lung of allergic subject or a joint of chronic rheumatoid arthritis subject. hGM-CSF mRNA is excessively detected in skin of individual with allergy. Furthermore, it is reported that the survival of monocyte, which is an inflammation outbreak cell of atopic dermatitis, is enhanced by GM-CSF production. (Bratton, D. L. et al., Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis. J. Clin. Invest., 95: 211-218, 1995).
Also, it is shown that GM-CSF stimulates proliferation of leukemic cells. Therefore GM-CSF is considered as a factor causing leukemia.
From the above reports, it is considered to be useful for antibody to bind to the over-expressed hGM-CSF in order to depress a biological activity, when a therapy is provided to treat various diseases caused by hGM-CSF.
The hGM-CSF activity is depressed to palliate disease symptom. The anti-hGM-CSF antibody has a high affinity and a high neutralizing capacity against hGM-CSF, and does not show immunological reaction. Therefore, it is estimated to be useful when the anti-hGM-CSF antibody is administered as an antibody agent for human.
So far, it has been reported that anti GM-CSF antibody is effective in a mouse asthma model (Cates, E. C. et al., Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism. J. Immunol., 173: 6384-6392, 2004. Ohta, K. et al., Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: essential role of GM-CSF. J. Allergy Clin. Immunol., 104: 1024-1030, 1999.). Also, it is reported that a model mouse for inflammatory arthritis will worsen its symptom, when GM-CSF is administrated. (Bischof, R. J. et al., Exacerbation of acute inflammatory arthritis by the colony-stimulating factors CSF-1 and granulocyte macrophage (GM)-CSF: evidence of macrophage infiltration and local proliferation. Clin. Exp. Immunol., 119: 361-367, 2000. Campbell, I. K. et al., Granulocyte-macrophage colony stimulating factor exacerbates collagen induced arthritis in mice. Annal. Res. Dis., 56: 364-368, 1997.). And, it is also reported that anti GM-CSF antibody is effective for palliating symptom (Cook, A. D. et al., Blockade of collagne-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res., 3: 293-298, 2001. Yang, Y. H. and Hamilton, J. A., Dependence of interleukin-1-induced arthritis on granulocyte-macrophage colony-stimulating factor. Arthritis Rheumatol., 44: 111-119, 2001.).
Antibodies blocking hGM-CSF reported does not have sufficient affinity and depressing capacity against hGM-CSF, although hGM-CSF is found to induce various diseases.
Therefore, the existing anti hGM-CSF antibodies were not able to inhibit a natural hGM-CSF biologic activity sufficiently (Japanese Patent Application No. H05-176792).
Also, polyclonal antibody and monoclonal antibody were derived from experimental animals, such as mice, rabbits and caprines. However, the obtained antibodies have the sequence specific for each kinds of animals. If they are administered to human body, human immune system recognizes the antibody as a foreign, and then, human anti-animal antibody response (that is, antibody produces its own antibody) is caused as a problem.
Therefore, it is strongly desired to develop an anti hGM-CSF antibody and its antigen binding portion derived from human monoclonal antibody without immunological response, so that they may be applied as a therapeutic agent with higher affinity, specificity and depressing capacity.
This invention focuses on providing a human monoclonal antibody and its antigen binding portion which excel in affinity and depressing capacity on hGM-CSF causing various diseases.